There is an increasing trend for drug abusers to abandon the more traditional routes of administration and adopt smoking and inhalation as the preferred modes for use. The emergence of smoking and/or inhalation of drugs such as PCP, cocaine and more recently methamphetamine has coincided with a dramatic change in their behavioral and toxicological potencies. Although there is strong evidence to suggest that smoking or inhalation enhances the abuse liability of some drugs, relatively little is known regarding the volatility of commonly abused drugs and the resulting pharmacological and toxicological consequences when they are either smoked or inhaled. A major goal of the present proposal is to determine the volatility and stability of drugs under conditions which mimic street use and to characterize the pharmacological potency of these drugs when they are exposed to animals via the inhalation route. This information will serve as a guide for predicting which other drugs can be smoked or inhaled. The first specific aim will be to determine the volatility as well as the stability of compounds from the major drug classes. These drugs will be heated in a glass pipe or smoked in cigarettes under conditions designed to mimic drug use so that volatilization/pyrolysis can be evaluated by HPLC and GC/MS analysis. The second specific aim will be to characterize the cocaine particle size and devise new procedures for improving our animal exposure system. The third specific aim will be to determine the pharmacological potency of these drugs when they are inhaled or smoked. Either spontaneous activity, motor coordination (inverted-screen test) or antinociception (tail-flick response) will be measured in mice which have been allowed to breathe the vaporized drug. Both time course and dose-responsiveness by the inhalation route will be compared to that obtained after intravenous injection. The forth specific aim will be to determine whether physical characteristics of drugs can be used to predict whether they may be volatilized. The approach will be to determine whether selected physiochemical properties (such as boiling point and vapor pressure) are indicative of the drugs which can be effectively volatilized in a glass pipe or smoked in a cigarette. Most of the physiochemical properties are known, except vapor pressure which we propose to determine. The last specific aim will be to characterize the behavioral and cardiovascular effects of cocaine administered acutely and chronically to rats. Our studies during the past grant period have revealed marked cardiovascular effects during a single exposure to cocaine vapor. On the other hand, our studies with chronic i.v. infusion demonstrated that sensitization developed followed by tolerance. In order to understand the consequences of long term exposure to cocaine vapor, we propose to fully examine the effects of cocaine on behavior, heart rate and blood pressure in rats exposed repeatedly to cocaine inhalation. These results will be compared to the effects after i.v. infusion.